This invention relates to apparatus and methods for coating a material. As will become apparent from the following description, the invention can be used in many coating applications, however one application to which the invention is particularly suited is in relation to the production of coatings for pharmaceutical capsules, tablets and like devices for the delivery of pharmacologically active substances (for either human or veterinary use) to a patient. The invention is especially suited for use in the production of pharmaceutical capsules, tablets and like delivery devices where the coating material for the pharmaceutical delivery device is intended to control or delay the timing of release of a pharmacologically active material contained within the xe2x80x9ccorexe2x80x9d of the device. While noting the invention""s suitability in a broad range of applications, it will be described in the following description with particular reference to the pharmaceutical coating application to which it is particularly suited.
In order for an effective dosage regimen to be delivered, many pharmaceutical substances must be administered according to exacting or occasionally, complex dosage regimes. Compliance with such regimes is particularly important in, for example, many third world countries, where patient compliance with a dosage regimen may be impaired due to the patient""s inability to understand the nature of the dosage regimen required, or the need for compliance. Similarly, the treatment of infants by a repeated course of injections can be particularly traumatic to the infant patients concerned, and the delivery of the regimen by a reduced number of doses whose release profile is controlled is particularly desirable. Another important scenario where controlled release delivery can be particularly advantageous (compared to repeated application of individual doses) is in veterinary medicine. Many animals react extremely adversely to the infliction of pain by (for example) repeated injections. In the veterinary treatment of animals, it can be particularly difficult to ensure that the animal has received the dosage required of the pharmaceutical agent concerned (particularly, for example, if the pharmaceutical agent involved must be administered in minute quantities, such as, for instance, with reproductive hormones used in animal husbandry). Repeated handling of an animal to administer drugs to it not only runs the risk that the animal will refuse to co-operate with the handler, and that the required dose of the drug may not in fact be delivered, but also, it runs the increased risk of injury to the animal handler that must administer the drugs.
The use of controlled release pharmaceutical delivery devices is therefore particularly desirable in many instances, including those described above. However, the delivery of drugs via controlled release regimens is not as widespread as might be hoped, because the production of suitable delivery devices for the controlled release of pharmacologically active substances is presently limited by the manufacturing methods 3 and production apparatus that have been used to date to make them.
Several methods have been employed to date in order to manufacture controlled release delivery devices to contain a dose of a pharmaceutical agent in the form of (for example) a tablet. One method that has been employed is injection moulding. This technique involves the injection of a heated coating material (typically, a pharmaceutically acceptable polymer) under pressure into a mould for a delivery device (in the form of, for example, part of a container). Once the coating material has cooled and solidified to a suitable extent, the mould is opened for ejection. The part container must then be filled with the pharmaceutical agent it is intended to contain, and it must then be sealed. This technique has significant limitations, particularly for the mass production of controlled release pharmaceutical delivery devices. For one thing, as explained above, it results in the production of only a partial container. This means that the process of producing a controlled release drug delivery device via the injection moulding method is a multi-step procedure, which requires sequentially (i) first, the production of a partial container, (ii) filling the partial container with the required dose of the drug it is intended to contain, and (iii) then sealing the container. This sequential, multi-step procedure is inefficient as a manufacturing process. It also involves a time delay between the initial step of manufacturing the partial-container and the subsequent steps of filling it with the pharmaceutical moiety and sealing the container, which can give rise to difficulties as regards ensuring that the finished product is sufficiently sterile for use in human or veterinary medicine.
A second technique is available for manufacturing pharmaceutical delivery devices in such a way as to overcome the sterility problems described earlier that affect the injection moulding procedure. In the pharmaceutical context, to date, the second technique appears to have been used solely in the manufacture of sterile vessels to contain liquids like physiological saline or water for injection. This second technique is referred to in the art as the xe2x80x9cblow-fill-sealxe2x80x9d (or the xe2x80x9cform-fill-sealxe2x80x9d) method. In this technique, a polymer (usually a plastics material) is melt-processed and extruded from a die to form a length of tube. When extruded, the tube is sufficiently hot to be malleable, but not so hot as to be liquid, and therefore, so as to be uncontrollable in the subsequent steps involved in the manufacturing process. A multi-piece die (containing a mould which encompasses the length of extrudate) then clamps around the length of extrudate (which is known as the xe2x80x9cparisonxe2x80x9d), thereby sealing one end of the parison, and leaving the other end gripped by the die, but slightly open. The parison (which at this stage of the process, remains hot and malleable) is a thin tube which is suspended within the mould cavity. Air is then injected into the interior of the parison so as to inflate it, so that it assumes the shape of the mould. The inflated parison is then filled with the desired contents by an injection process, and is then sealed. The die is then opened to release the finished product. The xe2x80x9cblow-fill-sealxe2x80x9d technique is similar in many respects to injection moulding. It is therefore subject to at least some of the same problems that apply to the injection moulding technique.
The present invention aims to avoid one or more difficulties associated with the prior art manufacturing techniques described above, and the apparatus used to perform them.
The invention generally provides a method of coating a material, the method including the following steps:
(a) forming a generally elongate coating structure, the coating structure having an internal cavity extending at least substantially along its length, and wherein the internal cavity of the coating structure is capable of receiving a core material;
(b) inserting a core material into the internal cavity of the coating structure;
(c) compressing the coating structure at a first location along its length so as generally to form a seal at that location; and
(d) compressing the coating structure at a second location along its length.
The method may be performed sequentially in the order of steps (a) to (d) set out above, or the steps of the method may be performed in another sequence. A preferred sequence is (from first to last step):
Step (a) (first step)
Step (c) (second step)
Step (b) (third step)
Step (d) (fourth step).
Preferably, the step of forming the coating structure involves extruding it from an extrusion means. In this embodiment of the invention, the coating structure must be an extrudable material, such as a plastics material which is amenable to processing techniques such as melt-processing and extrusion when heated. The extrusion means could for example, take the form of a die which extrudes the coating structure in lengths of any desired cross-sectional shape. Preferably, the cross-sectional shape of the coating structure formed by the extrusion means is circular, so that in its three-dimensional configuration, the coating structure generally has the appearance of a tubular structure. The coating structure""s cross-sectional shape could take any desired form however, including generally square, triangular, elliptical, ovoid or more complex shapes. The proviso here is that the cross-sectional shape must be a closed shape (such as the shapes described earlier), so that the extruded coating structure can be sealed when it is subjected to the compression steps of the method, described earlier. The cross-sectional shape adopted for the coating structure in any context may depend on the application to which the coated material produced by the coating method is to be put.
In one form of the invention, the coating structure comprises a single layer of the material from which it is formed. In other forms of the invention however, the coating structure may contain two or more layers of the same or of different materials from which it is formed. Forming the coating structure from two or more layers may be preferred where it is desired to control in a particular manner, the release profile of the core material from a finished container produced by the method. By forming the layers of the coating structure from materials having different degradation or permeability characteristics, a differential rate, onset or profile of release of the core material into a surrounding environment, as desired, could therefore be established.
Preferably further, in step (d) of the method, a seal is formed at the location of the second compression along the length of the coating structure, so as to define a closed container which comprises the coating structure sealed at two opposed ends, and containing the core material in its internal cavity. Preferably, the seal at each end of the container is formed by compressing two mutually opposed surfaces of the coating material so that they come into contact with one another in a sealing manner. A seal at any location could also be formed in other ways however, such as by heating the coating structure in addition to compressing it at the location concerned. The step of compressing the coating structure at any location could also involve cutting the coating structure at each of the first and second locations along its length, so as to define a free-standing container separated from the remaining coating structure from which the container was formed. Preferably further, such a container would have the appearance of a capsule, such as that of a conventional pharmaceutical capsule.
In some applications, it might be desirable to produce a container which is sealed at one end, but not at the other. In such a case, in step (d) of the method, the step of compressing the second location along the length of the coating structure could take the form of simply cutting it by using a cutting means, rather than forming a seal at that end. This version of the method might be used so as, for example, to form a pharmaceutical delivery device having one sealed end and one xe2x80x9copenxe2x80x9d end, so as to provide a delivery device which in use, would encourage the egress of the core material into a patient, from the xe2x80x9copenxe2x80x9d end of the device.
In other applications, it may be preferred to form a container which is completely unsealed at one end, and is xe2x80x9cgenerallyxe2x80x9d sealed at the other. By xe2x80x9cgenerallyxe2x80x9d sealing the container at the other end (meaning the first location along the length of the coating structure, in the description set out herein), and further, by reference in step (c) of the first aspect of the invention, mentioned earlier, to xe2x80x9cgenerally forming a sealxe2x80x9d, it is to be understood that a closure which falls somewhat short of a full or complete seal, is also comprehended. Thus, the formation of a partial seal at that location would be embraced by this feature of the invention.
Preferably further, the method would be suitable for continuous operation, or for repeated operation, along the length of the coating structure. In this way, the method C could be used to generate a desired number of individual containers each containing a length of the coating structure which are sealed as desired, and each of which contains an amount of the core material in its internal cavity. It is even further preferred that automation means be provided to operate the method, so that a convenient integrated method is provided for producing a desired number of containers as described above.
In a particularly preferred embodiment of the invention, the method is used to produce pharmaceutical delivery devices, such as coated capsules, coated tablets and the like. In this embodiment of the invention, the coating structure takes the form of a pharmaceutically acceptable substance or combination of such substances. Typically, the coating will comprise a pharmaceutically acceptable polymer or co-polymer, such as a plastics material. Particularly preferred substances for the coating material include polylactide-co-glycolide polymers, polyesters, polysaccharides, polyamides, poly (amino acids), poly (ortho esters), polyanhydrides, polyphosphoesters and polymers formed through combinations of chemical bonds (such as pseudo-peptides, poly (phosphoester-urethanes) and polydepsipeptides). The core material, in this embodiment of the invention, contains the pharmacologically active substance (for convenience called the xe2x80x9cbioactivexe2x80x9d in the remainder of this specification) whose release profile is desired to be controlled by the provision of the coating structure. The bioactive can be any suitable pharmacologically active substance. Typically, the bioactive would be a hormone or a vaccine, although the method is applicable to producing pharmaceutical delivery devices suitable for a broad range of bioactives, including natural, synthetic or recombinant pharmacological agents, food additives or food supplements, antigens, antibodies, cytokines, growth promotants, hormones, cancer cell inhibitory agents, immuno-suppressants or immuno-stimulants, anti-microbial agents (including antibiotics), anti-viral agents, vitamins, vaccines, minerals, and organic or inorganic nutrients. A bioactive core material for use in the invention may consist of one type of the aforementioned substances, or may include combinations of two or more such substances.
The bioactive (or a composite core material in which it is contained) could also take any number of physical forms, such as in the form of a tablet, a gel, a paste, as granules, in powder form, or a fluid, as well as others. The core material could also contain additional materials to the bioactive itself, including pharmaceutically acceptable carriers and excipients (including dispersion media, coatings, antibacterial, anti-fungal and/or anti-viral agents and the like, as well as salts such as di-calcium phosphate), inert (and pharmaceutically acceptable) materials designed to control further the release of the bioactive in a desired manner, and other like materials, as desired. For example, the core material could also contain a hydrophilic material to encourage the entry of water into the device (such as for example, a swelling agent, such as a xe2x80x9chydrogelxe2x80x9d) or a substance affecting the osmotic interaction of the core material with an external biological fluid. Additional components could include:
(i) binders, such as gum tragacanth, acacia, corn starch or gelatine;
(ii) disintegrating agents, such as corn starch, potato starch, alginic acid and the like;
(iii) lubricants, such as magnesium stearate;
(iv) explosive combinations (eg, citric acid/sodium carbonate);
(v) surfactant materials or other surface active molecules (eg, proteins, such as albumins, biological detergents and tweens);
(vi) solubility enhancers (eg, sodium citrate, sodium bicarbonate, magnesium carbonate);
(vii) absorbance enhancing agents;
(viii) lubricants;
(ix) flow promoters;
(x) plasticisers;
(xi) antisticking agents: and/or
(xii) anti-static agents.
As would be apparent to those skilled in the art, in pharmaceutical applications of the invention, all such additional components must be at least substantially pharmaceutically pure, non-toxic in the amounts used, and biocompatible with the bioactive(s) used and with the coating material.
The invention also provides an apparatus for coating a material, the apparatus including:
(a) means for forming a generally elongate coating structure having an internal cavity extending at least substantially along its length, and wherein the internal cavity of the coating structure is capable of receiving a core material;
(b) means for inserting a core material into the internal cavity of the coating structure;
(c) means for compressing the coating structure at a first location Q along its length so as generally to form a seal at that location; and
(d) means for compressing the coating structure at a second location along its length.
Preferably, the means for forming the elongate structure are extrusion means, as discussed earlier.
As explained above, the core material could take any number of physical forms, such as in the form of a tablet, a gel, a paste, as granules, in powder form, or as a fluid, as well as others. The means for inserting the core material into the coating structure could therefore take any number of forms, according to the nature of the core material to be inserted into the coating structure. For example, where the core material takes the form of a gel or paste, the means for inserting it into the coating structure could take the form of a nozzle designed to inject the core material into the internal cavity of the coating structure.
The means for compressing the coating structure at the first location could, for example, take the form of a mechanism for simply pressing two opposed surfaces of the coating structure together. Such means could also include means for forming a cut through the coating structure at that location. The means for compressing the coating structure at the second location could also take a similar form, however they could, if desired, take the form of a mechanism for forming a non-sealing open cut at the second location, so as to form a capsule with an open end at the second location.
Preferably, the apparatus is suitable for continuous, or repeated operation along the length of the coating structure, so as to lend itself to mass production of segments of a coated material, in the form of capsules or like devices.
The invention further provides a coated material produced by a process which includes the steps of:
(a) forming a generally elongate coating structure, the coating structure having an internal cavity extending at least substantially along its length, and wherein the internal cavity of the coating structure is capable of receiving a core material;
(b) inserting a core material into the internal cavity of the coating structure;
(c) compressing the coating structure at a first location along its length so as generally to form a seal at that location; and
(d) compressing the coating structure at a second location along its length.
Preferably, the coated material produced by the process takes the form of a coated tablet, coated capsule or a like device. Preferably further the coated structure is suitable for use as a controlled release device for delivering an amount of the core material in a predetermined manner. It is particularly preferred that in such a device, the core material contains a pharmacologically active substance, such as any of the bioactives described earlier. The process could also be configured to produce a coated material containing multiple units of the same bioactive, or a two or more units of different bioactives.